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Pleiotropic Effects of GLP-1 and Analogs on Cell Signaling, Metabolism, and Function - PubMed (original) (raw)

Review

Pleiotropic Effects of GLP-1 and Analogs on Cell Signaling, Metabolism, and Function

Jordan Rowlands et al. Front Endocrinol (Lausanne). 2018.

Abstract

The incretin hormone Glucagon-Like Peptide-1 (GLP-1) is best known for its "incretin effect" in restoring glucose homeostasis in diabetics, however, it is now apparent that it has a broader range of physiological effects in the body. Both in vitro and in vivo studies have demonstrated that GLP-1 mimetics alleviate endoplasmic reticulum stress, regulate autophagy, promote metabolic reprogramming, stimulate anti-inflammatory signaling, alter gene expression, and influence neuroprotective pathways. A substantial body of evidence has accumulated with respect to how GLP-1 and its analogs act to restore and maintain normal cellular functions. These findings have prompted several clinical trials which have reported GLP-1 analogs improve cardiac function, restore lung function and reduce mortality in patients with obstructive lung disease, influence blood pressure and lipid storage, and even prevent synaptic loss and neurodegeneration. Mechanistically, GLP-1 elicits its effects via acute elevation in cAMP levels, and subsequent protein kinase(s) activation, pathways well-defined in pancreatic β-cells which stimulate insulin secretion in conjunction with elevated Ca2+ and ATP. More recently, new studies have shed light on additional downstream pathways stimulated by chronic GLP-1 exposure, findings which have direct relevance to our understanding of the potential therapeutic effects of longer lasting analogs recently developed for clinical use. In this review, we provide a comprehensive description of the diverse roles for GLP-1 across multiple tissues, describe downstream pathways stimulated by acute and chronic exposure, and discuss novel pleiotropic applications of GLP-1 mimetics in the treatment of human disease.

Keywords: GLP-1; cell function and integrity; diabetes; metabolism; signaling.

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Figures

Figure 1

Figure 1

Commonly accepted GLP-1 signaling in the pancreatic tissue. Summary of the most commonly known signaling cascades activated by GLP-1 in the three different endocrine cell types α, β, δ, and their overall impact on diverse cellular processes.

Figure 2

Figure 2

GLP-1 signaling across different muscle types. Multiple signal transduction pathways and their net impact arising from GLP-1R stimulation in skeletal, cardiac, and both multi and single unit smooth muscle.

Figure 3

Figure 3

Active GLP-1 and its truncated products signaling in the liver. Active GLP-1 and its cAMP dependent pathways (solid arrows), as well as hypothesized (dashed arrows) truncated product induced signaling and their respective net effects.

Figure 4

Figure 4

Pleiotropic effects of GLP-1 signaling in the brain. GLP-1 and its analogs activate diverse signaling pathways in the brain, leading to a plethora of neuroprotective outcomes.

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